Several important retinal disease are caused by excess proliferation of cells in the eye;major ones which we plan to target with a novel pharmacologic approach include retinal detachment due to trauma and proliferative vitreoretinopathy as well as choroidal neovascularization in age related macular degeneration. One of the major problems in using local therapy for retinal diseases is the short half-life of most intraocular drugs that must be administered frequently. There is an important unmet need to develop a way to prolong the intraocular duration of intravitreally or similarly administered antiproliferative drugs. We have developed a novel chemical method of modifying nucleosides which provides for low solubility and long-acting antiproliferative or antiviral activity. Following a single intravitreal injection, we have already demonstrated persistent biological activity of prototype compounds for up to 20 weeks or longer. Our overarching goal is to develop long acting crystalline drugs that can be injected into the vitreous cavity in the eye in small volumes. Because these crystalline compounds are chemically designed to have low water solubility, they will act as extremely long acting anti-proliferative compounds which will help reduce retinal damage and vision loss from the above diseases and other retinal diseases. This grant focuses on diseases of proliferation but we stress that should this crystalline drug delivery system be successful in animal and in the future, in human studies, it will be able to be extended for treatment of many other intraocular diseases. This grant is a collaboration of two research groups, the Retina Research Laboratory at the Jacobs Retina Center (Drs. Freeman and Cheng) and Dr. Karl Hostetler in the Dept. of Medicine, both at UCSD. Dr. Hostetler's group is well known for synthesis and evaluation of lipid nucleoside analogs while Dr. Freeman's group is highly skilled in development and characterization of intraocular drugs and animal models of retinal disease. Together, we will synthesize and evaluate key lipid analogs of crystalline minimally soluble anti-proliferative compounds. Various in vitro and in vivo evaluations will determine the optimal structural and formulation variables to provide for a high therapeutic index and long intraocular half life. The best compounds and formulations will be tested in accepted animal models of the important retinal diseases mentioned above. This project may provide drugs with a prolonged duration of action which will be safe and have a high therapeutic index and may lead to new agents and treatment methods for important retinal diseases. Public Health Relevance: This research grant will allow the development of a long-acting intraocular injection that will prevent retina detachment and reduce the damage due to scarring from age-related macular degeneration. Our research group has discovered ways to modify small antiproliferative molecules so that they last for over 5 months in the eye and are thus optimal to help prevent these severe causes of blindness.